Higher dose of Hydroxyurea benefits Sickle Cell Anemia more, says study

By Esther Nakkazi

A study in Uganda that could revolutionalize the treatment delivery of sickle cell anemia in sub-Saharan Africa has shown that a higher dose of hydroxyurea is more effective for children.

Hydroxyurea, approved for sickle cell treatment in 1998 by FDA and was originally and it still is a cancer drug is the standard treatment for sickle cell disease in the U.S. and Europe but in much of sub-Saharan Africa, which has a high disease burden, it is not standard treatment. Sickle cell disease has been declared a major public health problem for sub-Saharan Africa by the World Health Organization.

The study published in the New England Journal of Medicine on 25th June 2020 shows that among children with sickle cell anemia in sub-Saharan Africa, hydroxyurea with dose escalation had superior clinical efficacy to that of fixed-dose hydroxyurea, with equivalent safety.

Researchers believe the study findings in Uganda will have a worldwide impact since an escalated dose is not currently the standard in some European countries and other regions.

In the randomized, double-blind trial, seeking to uncover the best treatment for sickle cell disease in sub-Saharan Africa, 200 children were divided into two groups with one group given a fixed dose of hydroxyurea, (approximately 20 mg per kilogram of body weight per day) and the other arm an escalating dose of (approximately 30 mg per kilogram per day).

The arm with the higher dose showed more benefit for the patients prompting the data and safety monitoring board to halt the trial early.

It was done by Indiana University School of Medicine (IUSM) in partnership with Robert Opoka, MMed, at Makerere University and Mulago Hospital in Uganda and funded by the Doris Duke Charitable Foundation and the Cincinnati Children’s Research Foundation.

“We hope this will change practice for the overwhelming majority of kids with sickle cell,” says Dr. Chandy John, a physician-scientist at IUSM’s Ryan White Center for Pediatric Infectious Diseases and Global Health and the study’s lead co-investigator.

“You increase the dose and make sure it’s safe at the higher dose because hydroxyurea has some side effects. But people didn’t want to do that in Africa, because it’s more complicated to do.”

The researchers also found that the escalating dose showed similar side effects as the fixed-dose and the financial cost of making the escalated dose standard in sub-Saharan Africa is not significant.

“To see this so unequivocally—to the point that the study’s [monitoring] board stopped the study early because they said the difference was so huge, it was not ethical to continue having two groups. None of us, including our sickle cell experts, expected the differences would be so huge. We were really shocked,” says Dr. Chandy John.

Researchers observed that the higher dose isn’t much more expensive, drug companies are subsidizing the medication, and the Ministry of Health of Uganda could classify it as an essential drug, meaning it would be provided for free.

However, the logistics of moving children in sub-Saharan Africa to the higher dose present challenges as it requires specialized providers - or pediatric hematologists.

“In rural areas, you can’t have a bunch of pediatric hematologists all over the country—that’s not practical, so training is needed for frontline healthcare workers in the basics of what to do with sickle cell,” says Dr. Chandy John.

The researchers' next set of studies is looking at very practical things about implementation where most of the affected children live. The study in Uganda was conducted at Mulago, a national referral hospital in the capital city, Kampala, but most kids with sickle cell are in rural areas with fewer resources.

“One study we’re proposing is…how do we practically implement this in lower-resource settings?,” says Dr. Chandy John. Sickle cell is a genetic disease that is not curable but preventable. In most communities in sub-Saharan Africa, there is a lot of ignorance about sickle cell disease with lots of myths and misconceptions about the disease.

At least 15,000 to 20,000 babies are born with sickle cell disease every year in Uganda, and 80 percent of them die before their 5th birthday. As a single disease, it could be killing more under-fives than any other although the statistics are scanty.

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